Susceptibility-guided bismuth quadruple therapies for resistant Helicobacter pylori infections

Abstract

Increasing Helicobacter pylori resistance to antibiotics has led to adoption of seven different bismuth quadruple therapies (BQT) in China without differentiation of first-line or second-line regimens. The objective of this study was to evaluate the efficacy of susceptibility-guided BQT for patients who had experienced previous treatment failures. A total of 133 patients was included and H. pylori was successfully cultured from 101 patients (75.9%) for subsequent antimicrobial susceptibility testing (AST). Based on the AST results, 88 patients completed one of five AST-guided 14-day BQT regimens: esomeprazole and bismuth colloidal pectin, along with either, amoxicillin and clarithromycin (EBAC), amoxicillin and levofloxacin (EBAL), amoxicillin and furazolidone (EBAF), amoxicillin and tetracycline (EBAT), or tetracycline and furazolidone (EBTF). H. pylori eradication rates were 100% for EBAC (5/5), EBAL (13/13), EBAF (14/14), and EBTF (43/43), but 76.9% for EBAT (10/13). The three patients that failed the EBAT regimen were all cured after subsequent treatment with the EBTF regimen. Our study demonstrates the excellent efficacy of the AST-guided BQT for referred H. pylori patients, and that the current EBAT regimen, used in clinics, needs to be optimized. In addition, 57 of the isolates were subjected to whole-genome sequencing. Analysis of the sequences revealed that point mutations in 23S rRNA correlated well with the phenotypic clarithromycin resistance with a concordance of 91.2%, while the concordance between phenotypic levofloxacin resistance and gyrA point mutations was 82.3%. This suggests that molecular testing is appropriate as a substitute for AST as a more rapid and cost-effective method for determining clarithromycin and levofloxacin resistance in Chinese patients.

Antibiotic Resistance of Helicobacter pylori Strains Isolated From Pediatric Patients in Southwest China

“…In view of the extremely high primary and secondary CLR resistance, the CLR-based regimens (even with the addition of bismuth) are no longer suitable as empiric treatment therapies for pediatric patients in Southwest China. However, of note is that if CLR is known to be susceptible by antimicrobial susceptibility testing, this antibiotic can be confidently prescribed to achieve successful H. pylori eradication ( Jones et al, 2017 ; Tang et al, 2020a ).…”

“…Given the limited number of antibiotics that are appropriate for H. pylori eradication in children, and the worldwide increase of antibiotic resistance, the recent ESPGHAN/NASPGHAN guidelines have recommended antimicrobial susceptibility testing to guide the H. pylori eradication treatment in children ( Jones et al, 2017 ). However, due to the fastidious culture of H. pylori and the lack of an easy and cost-effective testing method, antimicrobial susceptibility testing for H. pylori is almost universally unavailable in medical centers ( Montes and Pérez-Trallero, 2017 ; Li et al, 2019 ; Tang et al, 2020a , b ). Under such circumstances, profiling regional or population-specific antibiotic resistance patterns is of great importance in guiding the development of effective empiric treatment regimens.…”

Need for standardization and harmonization of Helicobacter pylori antimicrobial susceptibility testing

“…With whole‐genome sequencing and susceptibility testing of 59 H . pylori clinical isolates by E‐test, our group has recently shown that point mutations in 23S rRNA correlated 91.2% with the phenotypic clarithromycin resistance, while the gyrA point mutations correlated 82.3% with the phenotypic levofloxacin resistance 6 . In another recent study, the congruence between the phenotypic AST results by E‐test and the molecular susceptibility testing results by whole‐genome sequencing on 140 H .…”

“…The standard methods that have been used for H. pylori AST include agar dilution test, [9][10][11][12] disk diffusion test, [13][14][15][16][17][18] gradient E-test, 6,13,16 and broth microdilution test. [19][20][21][22][23] All these methods require isolation of viable H. pylori relying on specific microbiology skills in the clinical laboratory to grow this fastidious microaerophilic bacterium over a period of 1-2 weeks.…”

“…Compared to the standard AST methods, the molecular susceptibility testing of H. pylori does not require viable isolates, but relies on the detection of the presence of point mutations in the 23S rRNA and gyrA gene that are known to confer resistance to CLR and LEV. 6,8,[39][40][41] CLR resistance is caused mainly by the A2143G, followed by A2142G and A2142C mutations in the V region of the 23S rRNA gene, [41][42][43][44] and resistance to LEV is mainly attributed to point mutations DNA gyrase gene that lead to amino acid change at positions 87 and 91 of GyrA. 42,45,46 With whole-genome sequencing and susceptibility testing of 59 H. pylori clinical isolates by E-test, our group has recently shown that point mutations in 23S rRNA correlated 91.2% with the phenotypic clarithromycin resistance, while the gyrA point mutations correlated 82.3% with the phenotypic levofloxacin resistance.…”